(1) Field of the Invention
The present invention generally relates to compounds having pharmacological activity which are useful as pharmaceutical agents and, more particularly, as analgesic agents for the treatment of pain, and as prostaglandin-E.sub.2 antagonists for the treatment of prostaglandin-E.sub.2 mediated diseases, to pharmaceutical compositions containing one or more of these compounds, and to methods of treatment employing these compounds. More particularly, the present invention concerns substituted dibenzoxazepine compounds, pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and medical methods of treating pain and prostaglandin-E.sub.2 mediated diseases employing these compounds.
Analgesic compounds are agents which alleviate pain without causing a loss of consciousness and, thus, which are useful for treating pain.
The major classes of analgesic compounds include narcotic analgesics, or opiates, compounds which alleviate pain and induce sleep, and analgesic-antipyretic compounds, compounds which alleviate pain and reduce fever and inflammation, such as salicylates.
Although the efficacy of opiates in relieving pain is well established, the associated addiction liability of opiates is a distinct disadvantage of these compounds.
While salicylate and salicylate-like agents (non-steroidal antiinflammatory agents or NSAIDS) are also efficacious in relieving pain, they often exhibit undesirable side effects, such as gastrointestinal irritation, as with aspirin, allergic response, as with aspirin, and/or liver toxicity with extended use, as with acetaminophen.
The compounds of the present invention are neither opiates nor salicylates, and represent another class of compounds which are useful as analgesic agents.
(2) Description of the Related Art
U.S. Ser. No. 08/079,021 discloses 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- and/or 10-Substituted Dibenzoxazepine and Dibenzthiazepine Compounds, Pharmaceutical Compositions and methods for treating pain and prostaglandin-E.sub.2 mediated diseases.
U.S. Pat. No. 3,357,998 discloses derivatives of dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acids.
U.S. Pat. No. 4,170,593 discloses 1-(substituted amino)alkanoyl-2-(dibenzoxazepine-10-carbonyl) hydrazines and derivatives thereof.
U.S. Pat. No. 4,681,939 discloses 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, 2-[(substituted phenylsulfinyl)alkanoyl]hydrazides and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(substituted phenylsulfonyl)alkanoyl]hydrazides.
U.S. Pat. No. 3,856,782 discloses 2-benzyl-3H,7H-quino(8,1-cd)(1,5)benzoxazepin-3-one compounds.
U.S. Pat. No. 3,856,781 discloses 2-pyridylmethyl-3H,7H-quino(8,1-cd)(1,5)benzoxazepin-3-one compounds.
U.S. Pat. No. 3,809,698 and U.S. Pat. No. 3,875,166 disclose 3-(aminoalkoxy)-2,3-dihydroquinobenzoxa(or thia)zepine derivatives.
U.S. Pat. No. 3,534,019 discloses compounds which are hydrazides of tricyclic N-carboxylic acids.
U.S. Pat. No. 4,379,150 discloses dibenz[b,f][1,4]oxazepine derivatives which may have a heterocyclic ring present in the side chain at the 10-position of the molecule.
U.S. Pat. No. 2,852,528 discloses 11-unsubstituted 10-(tertiary aminoalkyl)-dibenzo-[b:f]-thia-[1]-aza-[4]-cycloheptadiene-[2:6] compounds.
6B 1 522 003 discloses 1-acyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydr azines.
European Patent Application Publication No. 0 480 641 A1 discloses tricyclic heterocycles which are stated to have anti-hyperalgesic properties.
European Patent Application Publication No. 0 534 667 A1 discloses tricyclic heterocycles which are stated to counteract mild to moderate pain by virtue of their anti-hyperanalgesic properties.
K. Nagarajan et al. in "Synthesis of 10,11-Dihydrodibenz[b,f][1,4]oxazepine Derivatives as Potential Anticonvulsant and Psychotropic Agents," Indian Journal of Chemistry, 24B, 840-844 (985), disclose several acyl, carbamoyl and thiocarbamoyl derivatives of 10,11-dihydrodibenz[b,f][1,4]oxazepine.
William E. Coyne et al. in "Anticonvulsant Semicarbazides," J. Med Chem. 11(6), 1158-60 (1968) disclose 10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazides.
Each of the documents described hereinabove discloses compounds which are structurally different from the compounds of the present invention. Thus, the compounds of the present invention are structurally distinct from that which has been described in the art.